This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Understanding individual differences in pain and analgesic responses has scientific and clinical implications. Evidence from both human and non-human species indicates inter-individual variability in basal nociceptive sensitivity and in responses to opioid analgesics. Evidence suggests that genetic factors contribute to individual differences in pain perception and analgesic responses. Over the past decade rodent literature has demonstrated genetic influences on nociceptive and antinociceptive responses. Limited research regarding genetic influences on pain and analgesia is available in humans;although, two recent studies have reported associations between specific single nucleotide polymorphisms-SNPs and experimental pain responses. Interestingly, multiple pain-related genetic associations identified in rodents and in humans have been sex-dependent. First, recent and emerging findings from quantitative trait locus-QTL mapping in mice will identify candidate genes that influence variability in nociceptive and analgesic sensitivity. Second, the association of these candidate genes to pain sensitivity and analgesic responses in humans will be determined using sophisticated, clinically relevant psychophysical procedures. Third, pharmacologic and molecular approaches will be used to elucidate the mechanisms underlying the newly discovered sex-related genetic association to pain and/or opioid analgesia. We plan to: characterize associations of the melanocortin-1 receptor gene-MC1R to basal pain sensitivity and opioid analgesia and to determine the sex-dependence of these associations;and characterize the association of the Mu-opioid receptor gene-OPRM1, the delta-opioid receptor gene-OPRD1, and the kappa-opioid receptor gene-OPRK1 to basal pain sensitivity and opioid analgesic responses. We believe that this model of interdisciplinary research represents the ideal pathway for gene discovery and translation to the clinical setting.